Even though hyperglucagonemia coexists with insulin deficiency in a variety of clinical conditions with accelerated urinary nitrogen excretion, and hypoaminoacidemia is characteristic of patients with glucagonoma, glucagon's effect on protein synthesis and degradation remains incompletely defined. The major objective of the present proposal is to gain better understanding on the effect of glucagon on protein synthesis and degradation in man, and to define its action on protein balance in relation to insulin. Our preliminary studies indicate that insulin causes positive protein balance in the postabsorptive state by inhibiting proteolysis and not by stimulating protein synthesis. The present study will measure the effect of insulin on protein synthesis in the postabsorptive man and also in subjects infused with a mixture of essential amino acids to determine the role of plasma amino acid concentration of insulin's protein synthetic action. Protein synthesis and proteolysis across leg or foream will be estimated by measuring the concentration and isotopic abundance of tyrosine in the arterial and venous plasma together with blood flow across leg or forearm during a continuous infusion of L-(ring 2H4) tyrosine. Whole body leucine flux will be determined from plasma (13C)KIC abundance at plateau, and fractional mixed muscle protein synthesis (FMPS) will be determined from the increment in (13C) leucine in mixed muscle protein obtained by serial muscle biopsies during a continuous infusion of L-(1-13C) leucine. Experiments will be performed in normal volunteers with infusions of somatostatin and different concentrations of insulin and glucagon to clearly define the effects of these hormones on protein synthesis and degradation. The effect of intra-arterial infusion of glucagon and insulin will be studied to determine whether an increase in the local concentrations of these hormones in forearm without any systemic changes affects protein turnover. Studies will also be done in diabetic patients to test the effect of insulin treatment and somatostatin infusion on FMPS. Results of protein synthesis estimated from different techniques will be compared to check the validity of the conclusions. These investigations will provide insight into the control of protein turnover in vivo and the cause of protein catabolism in diabetes and other catabolic conditions.